Transcript Genetic Predictors of Septic vs Benign Anal Disease in

Genetic Predictors of Quality of Life
Post Ileal Pouch Anal Anastomosis for
Ulcerative Colitis
TM Connelly MB, BCh, MS; B Sanders BS; A Berg PhD;
L Harris III BS, E Williams MD, S Deiling, BA; A Tinsley MD, MS
WA Koltun MD
No Disclosures
INTRODUCTION
 Total proctocolectomy and Ileal Pouch Anal
Anastomosis (IPAA) for ulcerative colitis (UC) allows
for the resection of the diseased rectum and colon
whilst preserving continence
 Procedure outcomes and patient satisfaction are
varied
 Many studies have attempted to predict pouch function
preoperatively or evaluate pouch function through
objective measures such as pouchitis and frequency of
bowel motions
Ileal Pouch Anal Anastomosis
INTRODUCTION
 Regardless of pouch function, patient
satisfaction or well-being post IPAA is what is
desired
 Factors to predict such well-being post IPAA
are not well defined
 We hypothesized that a correlation between a
genetic marker and pouch satisfaction may be
identifiable
AIM
To determine predictors of post
IPAA well-being or satisfaction in
the form of:
1. Demographic and
perioperative variables
2. Genetic markers
METHODS: Questionnaire Design
 To determine ‘patient satisfaction’ we created a
modified questionnaire based on the validated:
1. Modified Pouchitis Activity Score
2. IBD quality of life questionnaire (IBDQ)
 Added questions on steroid and antibiotic use
 Adapted to be pouch specific by adding the phrase
“Since your pouch operation…”
METHODS: Questionnaire Design
 The Modified Pouchitis Activity Score=4 questions on
clinical condition: stool frequency, rectal bleeding,
urgency and pyrexia
 IBDQ=32 questions covering 4 categories
•
•
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Bowel symptoms
Emotional well-being
Social well-being
Systemic symptoms
**These 4 categories were combined for an
‘overall QOL’ score
METHODS: Patient Selection
 The 220 adult UC-IPAA patients with stored DNA
samples were identified from our divisional Biobank
and mailed surveys
-Excluded pouch failure/excision patients
 14 surveys were returned to sender and 142 (69%)
patients responded
METHODS: Genotyping
 Patient DNA was genotyped on the HMC Division
of Colon and Rectal Surgery’s custom designed
Illumina® BeadExpress VeraCode platform
-307 IBD associated SNPs
 Genotyping was performed at the HMC Genomics
Core Facility
METHODS: Statistical Evaluation
Questionnaire Analysis
 For each category, the median overall score of all
patients was calculated
 Individual patient scores were then separated into
above or below the median
 Fisher’s exact test and the Mann Whitney test were
used
 Variables with a p<.05 in each category were entered
into multivariate analyses
METHODS: Statistical Evaluation
Genotyping Analysis
 Logistic Regression
 Bonferroni correction to correct for multiple
comparisons of 307 SNPs
RESULTS
Patient Demographics
FEMALE
39%
EX OR CURRENT SMOKER
41%
AGE AT DX (YEARS, SD)
32 ± 12
POUCH DURATION (YEARS, SD)
10 ± 6
DURATION BETWEEN DIAGNOSIS AND
COLECTOMY (YEARS, SD)
8±8
FACTORS CORRELATING WITH POOR
OVERALL QOL
UNIVARIATE
MULTIVARIATE
p value
OR
95% CI
p
Females
.003
2.6
1.1-6.0
.02
Readmitted within 30 days
post colectomy
.05
5.3
1.8-16.7 .005
History of pouchitis
.00008
5.6
1.12-20
.003
Intermittent pyrexia
.009
5.9
1.3-50
.03
Intermittent steroid use
.03
Intermittent antibiotic use
.04
Urgency
.004
FACTORS CORRELATING WITH POOR
OVERALL QOL SCORE
UNIVARIATE
MULTIVARIATE
p value
OR
95% CI
p
Females
.003
2.6
1.1-6.0
.02
Readmitted within 30 days
post colectomy
.05
5.3
1.8-16.7 .005
History of pouchitis
.00008
5.6
1.12-20
.003
Intermittent pyrexia
.009
5.9
1.3-50
.03
Intermittent steroid use
.03
Intermittent antibiotic use
.04
Urgency
.004
FACTORS CORRELATING WITH POOR
EMOTIONAL WELL-BEING
UNIVARIATE
p value
Urgent Colectomy
.0063
Readmitted within 30 days post
colectomy
.05
History of pouchitis
.00002
Intermittent pyrexia
.05
Intermittent steroid use
.03
Intermittent antibiotic use
.04
Urgency
.0065
Younger age at colectomy
.05
Shorter duration between UC
diagnosis and colectomy
.006
FACTORS CORRELATING WITH POOR
EMOTIONAL WELL-BEING
UNIVARIATE
MULTIVARIATE
p value
OR
95% CI
p
Urgent Colectomy
.0063
3.6
1.2-12.5
.02
Readmitted within 30 days post
colectomy
.05
5.6
1.8-20
.004
History of pouchitis
.00002
5.6
1.8-20
.004
Intermittent pyrexia
.05
Intermittent steroid use
.03
Intermittent antibiotic use
.04
Urgency
.0065
Younger age at colectomy
.05
Shorter duration between UC
diagnosis and colectomy
.006
FACTORS CORRELATING WITH POOR
SOCIAL WELL-BEING
UNIVARIATE
p value
Positive Smoking History
History of pouchitis
.02
.02
Intermittent pyrexia
.02
Urgency
.007
FACTORS CORRELATING WITH POOR
SOCIAL WELL-BEING
UNIVARIATE
MULTIVARIATE
p value
OR
95% CI
p
2.1
.99-4.5
.053
History of pouchitis
.02
.02
2.1
1.0-4.3
.04
Intermittent pyrexia
.02
Urgency
.007
Positive Smoking History
OVERALL QOL : GENETICS
SNP
Gene
p value
Bonferroni
corrected p
value
rs2279627
TNFSF14
.0001
.033
rs7837328
8q24
.00034
NSD
rs7014346
8q24
.0018
NSD
rs7712957
S100Z
.002
NSD
BOWEL SYMPTOMS: GENETICS
SNP
Gene
p
value
Bonferroni
corrected p
value
rs2279627
TNFSF14
.0001
.033
rs7712957
S100Z
.0004
NSD
rs1297265
Gene Desert
.002
NSD
rs9647373
CLDN1
.005
NSD
EMOTIONAL WELL-BEING: GENETICS
SNP
Gene
p value
Bonferroni
corrected p
value
rs7837328
POU5F1B
.00002
.0061
rs2279627
TNFSF14
.00014
.046
rs7014346
POU5F1B
.00014
.0146
rs7712957
S100Z
.002
NSD
TNFSF14 and POU5F1B
TNFSF14 (LIGHT)
-Stimulation of T cell proliferation
-VEGF induced apoptosis of macrophages for the resolution
of inflammation
-Increased in colonic mucosa of IBD patients
POU5F1 (OCT4)
-Embryonic stem cell pluripotency
-Inhibits the differentiation of progenitor cells
-Adult stem cell renewal
-Associated with UC and CRC
CONCLUSIONS:
CONCLUSIONS:
1. Worse overall QOL (emotional and social well-being + bowel
and systemic symptoms) was associated with:
Female gender, readmission post colectomy, pouchitis
intermittent pyrexia
SNP rs2279627 within the TNFSF14 gene
2. Poor emotional well-being was associated with:
Readmission post colectomy, pouchitis, urgent colectomy
SNPs within the TNFSF14 and POU5F1 genes
3. Poor social well-being was associated with:
Pouchitis and a smoking history
CONCLUSIONS:
 Outcomes of patients with pouches are largely
determined by postoperative variables
 However, genetic markers such as POU5F1 and
TNFSF14 SNPs are present preoperatively and may
potentially be used to assist in surgical decision
making
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